Radiosensitizing Effect of Trabectedin on Human Soft Tissue Sarcoma Cells

• Published in: International journal of molecular sciences 2022-11, Vol.23 (22), p.14305
• Main Authors: Loi, Mauro, Salvatore, Giulia, Aquilano, Michele, Greto, Daniela, Talamonti, Cinzia, Salvestrini, Viola, Melica, Maria Elena, Valzano, Marianna, Francolini, Giulio, Sottili, Mariangela, Santini, Costanza, Becherini, Carlotta, Campanacci, Domenico Andrea, Mangoni, Monica, Livi, Lorenzo
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Cell cycle; Chemotherapy; Cytotoxicity; DNA damage; DNA repair; Fibrosarcoma; Gene expression; Histone H2A; Humans; I.R. radiation; Immune system; Invasiveness; Leiomyosarcoma - drug therapy; Liposarcoma; Liposarcoma - drug therapy; Medical prognosis; PD-L1 protein; Radiation; Radiation-Sensitizing Agents - pharmacology; Radiation-Sensitizing Agents - therapeutic use; Radiosensitivity; radiosensitizers; Rhabdomyosarcoma; Sarcoma; Sarcoma - drug therapy; Sarcoma - pathology; Soft Tissue Neoplasms; Soft tissue sarcoma; Soft tissues; Synergistic effect; trabectedin; Trabectedin - pharmacology; Trabectedin - therapeutic use; Tumor Microenvironment; Tumors; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232214305

Trabectedin is used for the treatment of advanced soft tissue sarcomas (STSs). In this study, we evaluated if trabectedin could enhance the efficacy of irradiation (IR) by increasing the intrinsic cell radiosensitivity and modulating tumor micro-environment in fibrosarcoma (HS 93.T), leiomyosarcoma (HS5.T), liposarcoma (SW872), and rhabdomyosarcoma (RD) cell lines. A significant reduction in cell surviving fraction (SF) following trabectedin + IR compared to IR alone was observed in liposarcoma and leiomyosarcoma (enhancement ratio at 50%, ER50: 1.45 and 2.35, respectively), whereas an additive effect was shown in rhabdomyosarcoma and fibrosarcoma. Invasive cells' fraction significantly decreased following trabectedin ± IR compared to IR alone. Differences in cell cycle distribution were observed in leiomyosarcoma and rhabdomyosarcoma treated with trabectedin + IR. In all STS lines, trabectedin + IR resulted in a significantly higher number of γ-H2AX (histone H2AX) foci 30 min compared to the control, trabectedin, or IR alone. Expression of ATM, RAD50, Ang-2, VEGF, and PD-L1 was not significantly altered following trabectedin + IR. In conclusion, trabectedin radiosensitizes STS cells by affecting SF (particularly in leiomyosarcoma and liposarcoma), invasiveness, cell cycle distribution, and γ-H2AX foci formation. Conversely, no synergistic effect was observed on DNA damage repair, neoangiogenesis, and immune system.